Proliferation and differentiation of hepatic oval (stem) cells are regulated by a variety of factors, yet not completely understood. Lysophosphatidic acid (LPA) and sphingosine-l-phosphate (S1P) are {phospholipid growth factors}, which regulate cell proliferation and differentiation, increase motility, and even enhance survival in several cell types. Cellular effects of LPA and S1P are mediated mainly via G-protein coupled receptors encoded by Endothelial Differentiation Genes (EDG). We have found that induction of oval cell proliferation during liver damage was associated with the expression of several types of EDG receptors, predominantly in small oval cells. We, therefore, hypothesize that the EDG expression profiles and the corresponding cellular responses to EDG receptor ligands LPA and S1P are specific for hepatic stem cells at various stages of differentiation {to mature hepatocytes/cholangiocytes}. Moreover, we propose that differential expression of EDG receptors may be a necessary part of the mechanism responsible for the activation of hepatic stem cells. The goals of this project are to explore hepatic EDG receptor profiles {during liver injury in vivo}, and {determine oval cell responses and EDG-mediated signaling by LPA/S1P in vitro}. These goals will be achieved by pursuing two Specific Aims: (1) to characterize the pattern of hepatic EDG receptors at different stages of mouse chronic liver injury accompanied by proliferation of hepatic oval cells; and (2) To identify how EDG-mediated cell signaling by LPA/S1P will regulate hepatic oval cell activation, proliferation and differentiation in culture. The results will establish the expression profiles and localization of EDG receptors during hepatic oval cell proliferation and differentiation, and will determine intracellular signaling pathways of oval cell activation by LPA/S1P. Successful accomplishment of the project will provide novel information exploring lipid mediator signaling in stem cells, which will have a great value to develop new insights in stem cell biology. Finally, we believe that the data produced in the field of lipid signaling mechanisms during proliferation and differentiation of stem cells can be used to generate an R01, which will further expand our understanding of stem cell biology.